Abstract: Hereditary pancreatitis (HP) is an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) that eventually develops into chronic pancreatitis (CP). Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Importantly, HP patients have an extremely high risk of developing pancreatic cancer than other forms of CP. Unfortunately, the development of targeted preventive or therapeutic interventions for HP has been hampered by gaps in our understanding of its pathophysiology, which is mainly due to the practical difficulties in obtaining tissues from the pancreas during the early stages of the disease and the lack of animal models that recapitulate the human form of the disease. Recently we have developed a novel model of HP by expressing a common mutant of human PRSS1 (PRSS1R122H) in mice at a level equivalent to that found in human HP. This new model will provide us with a powerful tool to fulfill our long-term goal of understanding the initiating events of HP and developing specific strategies for its prevention and therapy. In this proposal, we will use our unique humanized pancreatitis model to test our central hypothesis that etiological factors interact with genetic changes to increase trypsin activity, which causes pancreatitis by cell-autonomous cell death signaling pathways and non-cell-autonomous inflammatory pathways. We will characterize these signaling pathways in the HP model and investigate their roles by both pharmacological and genetic approaches. We expect these studies will significantly improve our understanding of the specific role of intracellular human trypsinogen activation during the pathogenesis of HP and provide new insights for preventive and therapeutic interventions. Importantly, our novel clinically relevant model will provide a powerful tool for developing and testing such interventions.